To date, little is known about the underlying cellular and molecular mechanisms of progressive hearing loss (PHL) that affects our aging population. Degeneration of hair cells and spiral ganglia neurons (SGNs) are common phenotypes associated with PHL. The importance of K+ channels in the inner ear is underpinned by evidence that specific mutations of the channel result in degeneration of hair cells (HCs) and SGNs in humans. Here, we hypothesize that K+ channels in SGNs regulate the resting membrane potential and their excitability in order to modulate fluxes of intracellular Ca2+ (Ca2+i), which serves as a key second messenger, determining the development, function, and survival of SGNs. However, undue [Ca2+i] may induce neuronal death. We further predict that during aging and in several K+ channelopathies associated with progressive degeneration of SGNs, the expression of K+ channels are profoundly altered leading to membrane depolarization, excessive increased in Ca2+ influx, which triggers Ca2+- induced apoptotic neuronal death. The proposal will identify how homo- and hetero- multimers of K+ channels confer diversity of K+ currents, and how mutations of the pore- forming a-subunit may produce profound alterations of K+ currents. We will also learn how intracellular and single-pass accessory subunits control K+ channels in SGNs. Five specific aims consider; what elementary features of K+ channels in SGNs confer their roles as K+ transporters (Aim 1); what K+ channel subunits constitute native SGN K+ currents (Aim 2); how soluble cytoplasmic proteins, K+ channel interacting proteins (KChIP), regulate the surface expression and properties of K+ channel currents (Aim 3); how single-pass subunits of K+ channels, KCNEs, dictate specific K+ channel functions in health and disease (Aim 4); and the ensuing biochemical and functional changes that occur during aging (Aim 5) that mediates PHL. The proposal uses normal and genetically altered mice as the experimental models, and exploit classical techniques (electrophysiology, biochemistry and electron microscopy) and novel strategies made powerful by recent advances in molecular biology (e.g, siRNA knockdown and viral- mediated gene transfer). Of particular importance to auditory science is the possibility that a rational design of K+ channel subtype-specific drugs may be realized, as our understanding of the gating, permeation, and pharmacology of the channels becomes more refined. PUBLIC HEALTH RELEVANCE: Spiral ganglia neurons (SGNs) are the primary neurons that convey sound information in the form of electrical signals from the inner ear to the brain. These neurons transmit sound information with remarkable precision and sensitivity. Several diseases and aging are associated with progressive degeneration of SGNs leading to hearing loss. Our objectives are to understand how K+ channel proteins regulate the electrical activity and biochemistry of SGNs. Studies from our group and others have demonstrated that during the aging process and in several diseased states the expression of K+ channels are altered and may underlie changes in electrical activity in SGNs that leads to degeneration of the neurons. At the cellular and molecular level, we know very little about the how K+ channels and their alterations trigger SGN degeneration, despite its potential therapeutic ramifications. Strong evidence from data from our laboratory and others motivates our overall hypothesis. We hypothesize that K+ channels in SGNs regulate their electrical activity. However, during aging and several diseased states the functions of these K+ channels are altered, triggering neuronal death. Our ultimate goal is to design drugs that may help alleviate/prevent neuronal death in our aging population and in several diseases affecting the inner ear.